Dexamethasone Suppresses Vascular Smooth Muscle Cell Proliferation

Reil, Todd D.; Sarkar, Rajabrata; Kashyap, Vikram S.; Sarkar, Minakshi; Gelabert, Hugh A.

doi:10.1006/jsre.1999.5665

Cited by 35 publications

(37 citation statements)

References 24 publications

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“…Among the wide spectrum of biological actions of glucocorticoids, dexamethasone has been shown to inhibit vascular cell proliferation [46]. The antiproliferative findings in this study are consistent with a study of prednisolone on platelet-derived growth factor-stimulated PASMCs from PAH patients [47], although that study used much higher doses (equating to 3610 -5 and 3610 -4 M dexamethasone).…”

Section: Discussionsupporting

confidence: 87%

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

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Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points.Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg?kg ) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression.Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro.Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

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Section: Discussionsupporting

confidence: 87%

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

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“…However, there are two pieces of evidence that suggest that these oscillations in RPF are cell-cycle-independent. Firstly, it has been shown that treatment of mammalian cells with dexamethasone arrests the cell cycle in a concentration-dependent manner (Reil et al 1999). Secondly, treatment of mammalian cells with dexamethasone at lower concentrations will synchronize the cell cycle with a non-24-h period (Yeom et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Ribosome profiling reveals an important role for translational control in circadian gene expression

et al. 2015

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Physiological and behavioral circadian rhythms are driven by a conserved transcriptional/translational negative feedback loop in mammals. Although most core clock factors are transcription factors, post-transcriptional control introduces delays that are critical for circadian oscillations. Little work has been done on circadian regulation of translation, so to address this deficit we conducted ribosome profiling experiments in a human cell model for an autonomous clock. We found that most rhythmic gene expression occurs with little delay between transcription and translation, suggesting that the lag in the accumulation of some clock proteins relative to their mRNAs does not arise from regulated translation. Nevertheless, we found that translation occurs in a circadian fashion for many genes, sometimes imposing an additional level of control on rhythmically expressed mRNAs and, in other cases, conferring rhythms on noncycling mRNAs. Most cyclically transcribed RNAs are translated at one of two major times in a 24-h day, while rhythmic translation of most noncyclic RNAs is phased to a single time of day. Unexpectedly, we found that the clock also regulates the formation of cytoplasmic processing (P) bodies, which control the fate of mRNAs, suggesting circadian coordination of mRNA metabolism and translation.

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“…In SMC culture, Dex has been shown to inhibit cell cycle progression, mitogen-induced proliferation, protein synthesis, and PDGF A-chain expression (31,39,41,50). Although the predominant concentration used for most studies has been 100 nM, maximum effects have been seen with as little as 10 nM (31).…”

Section: Discussionmentioning

confidence: 99%

“…Although the predominant concentration used for most studies has been 100 nM, maximum effects have been seen with as little as 10 nM (31). Inhibition of SMC growth has most often employed a 24-h pretreatment; however, recent studies have suggested that 6 to 8 h may be necessary to effectively inhibit vascular SMC growth (50) and as little as 1 h may suffice to inhibit airway SMC proliferation (58). In the present study, as well as in our previous study of cultured SMC (49), the maximum effect on MCP-1 mRNA was also seen with concentrations as low as 10 nM.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Dexamethasone-Sensitive RNA-Destabilizing Region on Rat Monocyte Chemoattractant Protein 1 mRNA

Poon

Liu

Taubman

1999

Molecular and Cellular Biology

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Glucocorticoids are potent anti-inflammatory agents widely used in the treatment of human disease. We have previously shown that the inflammatory cytokine monocyte chemoattractant protein 1 (MCP-1) is regulated posttranscriptionally by glucocorticoids in arterial smooth muscle cells (SMC). To elucidate the mechanism mediating this effect, in vitro-transcribed radiolabeled MCP-1 mRNA was incubated with cytoplasmic extracts from SMC and analyzed by gel electrophoresis. Extracts from SMC treated with platelet-derived growth factor (PDGF) did not degrade the transcripts for up to 3 h. In contrast, extracts from cells treated with 1 M dexamethasone (Dex) alone or in combination with PDGF degraded the probe with a half-life of Ϸ15 min. Dex had maximal effect at concentrations above 0.01 M and was effective on both rat and human MCP-1 transcripts. By deletion analysis, the Dex-sensitive region of the MCP-1 mRNA was localized to the initial 224 nucleotides (nt) at the 5 end and did not involve an AU-rich sequence in the 3 untranslated end. The 224-nt region conferred Dex sensitivity to heterologous mRNA. These studies provide new insights into the molecular mechanisms underlying the effect of glucocorticoids on gene expression.Glucocorticoids are potent anti-inflammatory agents used to treat a wide variety of diseases. While considerable information is available on the cellular events mediating glucocorticoid activity (reviewed in references 4 and 8), the mechanisms involved in their anti-inflammatory effects remain to be fully elucidated. One component of the inflammatory response of particular importance in the arterial wall is the recruitment and adhesion of monocytes/macrophages to sites of inflammation and injury. Macrophages are the primary source of cholesterolrich foam cells seen throughout the atherosclerotic plaque (20,24,28). Macrophages also produce a variety of cytokines and growth factors (15), which may stimulate a proliferative and migratory response at sites of injury. Macrophages are phagocytic and produce metalloproteinases, which degrade extracellular matrix proteins; these may play a role in destabilizing the atherosclerotic plaque or facilitating cellular migration (23,30,42). Finally, macrophages are an important source of tissue factor (32,51,63), the initiator of coagulation, and thus may play an important role in mediating plaque thrombosis.Long-term glucocorticoid treatment has been reported to decrease macrophage accumulation and plaque size during the development of atherosclerosis (38). We have recently shown that dexamethasone (Dex) markedly inhibited the accumulation of macrophages and the development of intimal hyperplasia in the femoral arteries of cholesterol-fed, balloon-injured rabbits (47a). In addition, treatment of rat aortic smooth muscle cells (SMC) with Dex completely blocked the growth factor-mediated accumulation of monocyte chemotactic activity in the culture medium (48).Monocyte chemoattractant protein 1 (MCP-1) is a low-molecular-weight cytokine secreted by endothelial cel...

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Dexamethasone Suppresses Vascular Smooth Muscle Cell Proliferation

Cited by 35 publications

References 24 publications

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Ribosome profiling reveals an important role for translational control in circadian gene expression

Identification of a Novel Dexamethasone-Sensitive RNA-Destabilizing Region on Rat Monocyte Chemoattractant Protein 1 mRNA

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